The Medical Detectives Volume I

by Berton Roueche

  Stone's triumphant report, which was presently published in the Philosophical Transactions of the Royal Society, had two triumphant results. The first, and by far the more direct and immediate, was a burst of corroborative clinical tests that promptly returned the willow to a reputable place in the professional medicine chest. The other was the introduction of the willow into the laboratories of scientific chemistry, which were then just opening. There, in the first decades of the nineteenth century, it happened to catch the eye of a cosmopolitan company of investigators whose particular interest was the chemical composition of medically useful plants. Their attention, once focused, was almost at once productive. The effective essence of willow bark was identified by the Italian chemists Fontana and Brugnatelli in 1826. Three years later, a French experimental pharmacist, Henri Leroux, accomplished its isolation. In 1838, the extraction of salicylic acid was accomplished by the Italian chemist Rafelle Piria. At about the same time, in Switzerland, an apothecary named Pagenstecher found that it could also be obtained from meadowsweet and bridal wreath, and his provocative find was closely followed by a succession of explorations, in England, Germany, and elsewhere, that quickly established its presence in a multitude of other plants. The inquiry then came to a halt. For it was almost as quickly established that salicylic acid, despite its abundance of sources, was too costly to extract to be of much practical use. Also, for the moment, the investigators had satisfied their curiosity.

  Their curiosity remained quiescent for close to a generation. It revived, like the whole of organic chemistry, with the stentorian enunciation, by the German chemists Friedrich Wohler and Justus von Liebig, of the theory of synthesis, or the interrelation of organic and inorganic substances. Among those who heard their call was a professor of chemistry at the University of Leipzig named Hermann Kolbe. To Kolbe, the sound was a summons. It summoned him to work, and to fame. In 1874, after a period of patient stalking, he emerged from his laboratory and held up to view in the pages of the Journal fur praktische Chemie an economical procedure for the production of synthetic salicylic acid. The importance of Kolbe's achievement, which posterity has recorded as a milestone in the history of synthetics, was readily grasped by all but the most myopic, and the halls of progressive chemistry rang with appreciative applause. So, understandably, did those of contemporary medicine, but only for a time. The hopes it excited in medical science soon and suddenly withered. Although Kolbe had solved one practical problem, his solution brought another to light, which revealed itself at the first round of clinical trials. Pure salicylic acid, though a model of strength in dulling pain and banishing fever, was by no means a model drug. Its salubrious powers were more than offset by its high degree of toxicity. Large or frequent doses, the reporting clinicians agreed, almost always resulted in nausea, often in spasms of vomiting, and sometimes even in coma. The inquiry once more shifted its course. What was needed now, its participants perceived, was a neutralizing agent, or buffer. That meant searching out some substance that would combine with salicylic acid (not all elements are physiologically compatible), render it sufficiently bland for general clinical use, and yet leave unimpaired its therapeutic vigor. The chemists' resilience, for once, was fully and finally rewarded. There are, to the best of scientific knowledge, just three compounds that meet these requirements with anything approaching precision, and all were known and in service before the end of the century. One of them—sodium salicylate—turned up at the very first cast, in 1876. In 1885, the Polish pharmacologist Marcellus von Nencki identified phenyl salicylate as another. The third is acetylsalicylic acid. It was introduced in 1899.

  Acetylsalicylic acid had its pharmacological origin in the laboratories of Friedrich Bayer & Company, later a subsidiary of I. G. Farbenindustrie, near Diisseldorf. It was first developed there, early in 1899, by a young research chemist named Felix Hoffmann. Hoffmann was not, nor did he claim to be, the actual discoverer of acetylsalicylic acid. That distinction had been achieved some forty years before by an Alsatian chemist named Charles Frederic von Gerhardt. What Hoffmann discovered was its usefulness. Von Gerhardt had encountered acetylsalicylic acid in 1853 while exploring the interaction of various salts and acids, but he considered it merely a novelty. Like Paul Gelmo, the precocious Viennese student who in 1908 casually created and indifferently abandoned the coal-tar derivative known since its recreation (by Gerhard Domagk, in 1933) as sulfanilamide, von Gerhardt was born too soon to comprehend what he had wrought. Hoffmann, like Domagk, was more favorably placed. His accomplishment, however, can be laid only partly to the instructive passage of time. He had other, less common advantages. Of these, two were decisive. One was a uniquely compelling source of inspiration in the person of his father. The elder Hoffmann was an invalid, a racked and crippled victim of rheumatoid arthritis. Of the remedies then at hand, including both sodium and phenyl salicylate, none could give him any adequate relief, and his life had become an agony. This wrenched the son from his workaday studies and drove him in search of some effective medicament. Hoffmann's other great gift was good luck. This guided his steps past the standard works in the scientific library to a compendium of chemical freaks and drones, and enabled him to find what he was looking for. His next move was conventional. Having satisfied himself, by laboratory test and domestic trial, of the worth of acetylsalicylic acid, he assembled his notes and carried them dutifully to the Bayer Company's director of pharmacological research. That was Heinrich Dreser, the architect of, among other things, diacetylmorphine, or heroin, and then an imposing figure in European science. Dreser reacted to the data set before him in a manner befitting his rank. He took one look, and took over. It was he who piloted acetylsalicylic acid through its first full-dress clinical evaluation. It was he who discarded its natural name as being hard to pronounce, hard to remember, and impossible to patent, and replaced it with the commercially seemlier "Aspirin." And it was he who wrote, and cheerfully signed, the pioneering report, confidently entitled "Pharmakologisches uber Aspirin (Acetylsalicylsaure)," whose publication in Pfliigers Archiv fur die gesamte Physiologie des Menschen und der Tiere first brought the compound to the attention of medicine. That was toward the end of 1899. Its merits took it from there.

  Acetylsalicylic acid (as most clinicians still choose to call it), or aspirin (the name practically everyone else prefers), or Aspirin (as its original proprietors were profitably privileged to insist on its being called until the general expiration of their patents around 1917), is an extraordinary drug. Almost everything about it is unusual. It comes, for one thing, impressively close to being the oldest therapeutic agent in continuing active demand. Only such venerable specifics as quinine (for malaria), colchicum (for gout), digitalis (for cardiac weakness), and, perhaps, the bromides (for relief of nervous tension) are of greater age and durability. Unlike these tottering centenarians, however, it has more than merely held its own against the massive ingenuities of mid-twentieth- century pharmacology. In 1935, the annual consumption of acetylsalicylic acid in the United States was estimated at four million pounds. By 1944, it had risen to nearly eight million. According to the least galvanic estimates, it now exceeds eleven million pounds, or, in terms of the standard dosage, approximately sixteen billion five-grain tablets. The true figure is probably well in excess of that, for, in general, such estimates refer only to the acetylsalicylic acid that is marketed under the name of aspirin. They seldom include that contained in the several more recently developed proprietary preparations—Bufferin, Anacin, Empirin, and Alka-Seltzer, among others—of which it is a major ingredient. The popularity of acetylsalicylic acid is almost equally immoderate elsewhere in the world. In some countries, notably Canada and those of Western Europe, it has, if anything, inspired an even fiercer veneration (England, for example, with hardly a fourth the population of the United States, consumes at least three million pounds of it a year), and there are no countries in which it is unknown, unappreciated, or unavailable. It is, in fact, the most widely used drug
on earth. It is also the cheapest (a five-grain tablet costs about half a cent), one of the safest (many aspirant suicides have survived doses of more than two hundred grains), and, among drugs of a comparable nature, including its companion salicylates, without much doubt the best. Some authorities go further than that. They consider it the most generally useful drug in the entire armamentarium of medicine.

  It is not hard to understand why. The great majority of drugs, as the heft of the modern pharmacopoeia is enough to suggest, are more conspicuous for the refinement than for the variety of their therapeutic feats. Hundreds, like insulin (the specific for diabetes melitus) and heparin (an anticoagulant), are limited in usefulness to one particular function, and there are many hundreds more whose present scope is only a trifle less narrow. Even the widest- ranging antibiotics, for all the multiplicity of horrors—anthrax, brucellosis, endocarditis, meningitis, tularemia, and syphilis, among others—over which they have an almost sovereign domination, are anything but widely effective. Their range is wholly confined to diseases of infectious, or microbial, origin. Acetylsalicylic acid is differently endowed. Although it is incapable of mastering any disease, it possesses a masterful sweep. Few drugs embody more, or more various, powers. As an analgesic, an antipyretic, an antirheumatic, and—or at least so a recent study at the Boston University School of Medicine, in which it appeared to show a marked capacity for preventing the recurrence of kidney stones, would suggest—an anticalculus, its palliative reach embraces practically all the smaller miseries, as well as some of those of considerable stature, that try the human race.

  Just how acetylsalicylic acid performs this symphony of services has yet to be fully fathomed. Fifty years of investigation have illuminated little more than the general route it follows through the body. Salicylic acid, the active principle of the drug, is absorbed directly from the small intestine into the blood stream. It remains there, moving with the current of the circulation, for, in most cases, ten to fourteen hours. It then passes into the kidneys and is excreted in the urine. It is also known to form in the kidneys a compound called glucuronide, whose presence increases the solubility of calcium—a phenomenon that would seem to explain its apparent anticalculous action. The essential physiology of the acid is otherwise very largely opaque. About the only further probability is that each of its distinctive effects is achieved by a different mechanism. There is no possible functional connection between its capacity for generating glucuronide and any of its other attributes, and it seems almost as certain that the processes by which it blocks pain, reduces fever, and suppresses joint inflammations are also completely unrelated. Of these three established powers, the first is the least mysterious. Most physiologists believe that the site of salicylic acid's analgesic action is the thalamus, the chief sensory reception center, located in the forebrain. There, in some obscure manner, the acid (or impulses set in motion by it) impedes the normal transmission of stimuli conveying the sensation of pain. The best evidence suggests that acetylsalicylic acid has the power to raise the threshold against pain perception by about thirty-five per cent. "A very small dose of aspirin has a measurable effect in raising the pain threshold," Stewart Wolf, head of the Department of Medicine of the University of Oklahoma School of Medicine, and Harold G. Wolff, professor of medicine at the Cornell University Medical College, noted in a recent monograph. "Increasing the dose has a progressively greater effect up to about ten grains, beyond which no additional pain- killing effect is manifest, although larger doses do somewhat prolong the duration of effect. With ten grains of aspirin, maximum effect is achieved in about one and a half hours. Thereafter its action in raising the pain threshold begins to dwindle. The effect can be kept at a peak most satisfactorily not by giving larger doses but by frequently repeating the ten-grain dose, say at two- hour intervals. . . . Combinations of analgesic drugs are no more effective than is the single strongest drug in the combination. The most that can be achieved in terms of deadening pain is the effect of ten grains of aspirin." This, of course, is not to say that acetylsalicylic acid is the strongest of all analgesics. It is merely the strongest that can be safely used without medical supervision. Morphine, for example, is capable of raising the threshold against pain perception as high as seventy per cent, but it also affects pain reaction; that is, it simultaneously blocks the passage of stimuli conveying such sensations as tension and anxiety. The artificial avoidance of tension and anxiety is the basis of addiction. Acetylsalicylic acid has no effect whatever on pain reaction.

  Almost nothing is known about the way acetylsalicylic acid functions as a febrifuge. There are no absolute data on the dynamics involved, and only a few reasonably firm hypotheses. The firmest of these concern the general procedure by which a reduction of fever is accomplished. It was once held that the phenomenon could be ascribed largely to a braking action on the machinery of heat production. Recent research has substantially altered this view. The explanation now in vogue suggests that antipyresis results primarily from a simple quickening of the body's natural facilities, for releasing excessive heat—the peripheral blood vessels and the sweat glands. Its ultimate cause, as currently envisioned, is more complex. Animal experiments have demonstrated that, contrary to snap assumption, this hyperactivity is induced not by direct stimulation of the superficial thermostatic apparatus but indirectly, through the central nervous system. In the opinion of most investigators, the specific focus of impact is probably one or another of the numerous regulatory nuclei that are clustered near the midbrain. Beyond this point, however, all suppositions falter. The nature of the power that acetylsalicylic acid has over these nuclei eludes even the nimblest imaginations, except for one twilit hypothesis: The control it exerts would seem to be somewhat less than total. For, as a mountain of empirical evidence makes clear, its influence is limited to remission of fever. It is peculiarly, and providentially, incapable, even in massive doses, of forcing the temperature of the body below 98.6 degrees, or normal.

  Everything about the antirheumatic powers of acetylsalicylic acid is elusive. No one has any understanding of their fundamental character. It can be said only that they very definitely exist. They are, in fact, so plainly pronounced that acetylsalicylic acid has stood unchallenged for almost half a century as the drug of majority choice in the symptomatic treatment of rheumatic fever, rheumatoid arthritis, and other inflammations of connective tissue. Its position, though violently shaken by the cyclonic appearance of cortisone and ACTH in 1949, is still far from insecure. Many clinicians—especially in Britain, where the adrenocortical hormones were welcomed with a rather less millennial euphoria than in their native America—have never ceased to prefer it. "Modern hormone therapy notwithstanding, salicylate, either as the sodium salt or as acetylsalicylic acid—remains the safest and most satisfactory drug in the routine treatment of rheumatism," Stanley Graham, professor of child health at the University of Glasgow, wrote in a recent report to the British Medical Journal. Much the same opinion has been expressed by William McJefferies, assistant professor of medicine at the Western Reserve University School of Medicine, in the New England Journal of Medicine. "Although ACTH, cortisone, or hydrocortisone in adequate doses can at least temporarily control the symptoms of rheumatoid arthritis in practically every case," Dr. Jefferies observed, "the chronic nature of this disease and the hazards of prolonged maintenance of steroid therapy make it generally advisable to try other accepted methods of treatment, such as salicylates and physiotherapy, first." To these views, Sir Henry Cohen and his fellow members of the Joint Committee of the (British) Medical Research Council and Nuffield Foundation on Clinical Trials of Cortisone, ACTH, and Other Therapeutic Measures in Chronic Rheumatic Diseases, which recently completed a definitive two- year study, have added the opinion that "for practical purposes there has been remarkably little to choose between cortisone and aspirin in the management of [rheumatoid arthritis]." Except, of course, as the committee must have felt it unnecessary to point out, in terms of price (the
average effective dose of cortisone costs almost a dollar) and prudence.

  Although, because of its low toxicity, its inability to dull the pain-reaction sense, and its lack of any effect on normal body temperature, acetylsalicylic acid ranks high among the safest of chemotherapeutic agents, it is by no means entirely innocuous. It has its savage side. Like most substances, including many foods, it can produce a variety of allergic reactions—dizziness, ear ringing, nausea, vomiting, skin eruptions, asthmatic seizures, muscular spasms—in susceptible individuals. Some of these idiosyncratics are so exquisitely responsive that a single grain can have a shattering, or even a fatal, impact. Cases have been reported of people's being thrown into convulsions upon receiving a blood transfusion from a donor whose gift contained a just perceptible trace of the salicylate radical. Its touch can also dishevel constitutions that are not congenitally vulnerable. The cruel acidity that seriously flaws most salicylates is not altogether neutralized in the acetylsalicylic compounds. Chemistry has merely blunted its bite. There are certain diseases—peptic ulcer, for example, and coronary thrombosis—in which the use of acetylsalicylic acid may precipitate such complications as acute dyspepsia, prolonged retching, and hemorrhage. A general debility, such as that brought on by many essentially trivial ailments, may also, in a manner not yet fully understood, magnify its pernicious powers. It is, in addition, corrosive enough to sometimes enfeeble the most robustly well. No one can long consume immoderate amounts of aspirin (fifty or more grains a day) without suffering some degree of intoxication, and even a tablet or two, if swallowed whole on an empty stomach, often will cause a twinge of sour, heartburning discomfort. For all their abundance, however, the reprehensibly rash are not particularly prominent among those whom acetylsalicylic acid most commonly shakes or sickens. Nor, since they are generally made wary by early experience or experienced counsel, are the sensitive or the unwell. Its usual victims—in this country, at least—are children. According to the United States Food and Drug Administration, thousands of cases of salicylate poisoning of sufficient seriousness to require the services of a physician occur in the United States every year. In 1952, for instance, the total, including a hundred and thirteen cases that ended in death, reached nearly seventeen thousand. Of that number, nearly three fourths, or more than thirteen thousand, were children—young children. Hundreds were mere infants, a year old or less, and none was more than five. Most of them, like the boy whose case was brought to the attention of Dr. Jacobziner that afternoon last May, were around three.